Dendritic cells in cancer immunotherapy Aimin Jiang
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1 Dendritic cells in cancer immunotherapy Aimin Jiang Feb. 11, 2014
2 Dendritic cells at the interface of innate and adaptive immune responses
3 Dendritic cells: initiators of adaptive immune responses Dendritic cell immunity MHC-II TCR Naive T cell tolerance
4 DC cancer vaccine A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains a small amount of an agent that resembles a microorganism. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. It often contains an adjuvant that activate DCs. Could be preventive (humoral) or therapeutic (celleluar, cancer vaccine)
5 Why do we need cancer vaccine? Immune responses against cancer cells were not strong enough. Immune system can reject tumors!!! Passive Immunotherapy: Transfer of T cells or antibodies ---- no memory T cells Active immunotherapy: DC vaccine tumor-specific effector and memory T cells
6 Three approaches of DC-based cancer vaccine Advantage: safe, some clinical responses, potential Dendreon s Provenge (DCs) was approved for prostate cancer treatment.
7 Dendritic Cells as Therapeutic Vaccines: Original Concept (circa 1992) Goal: Induce antitumor (or antiviral) immunity using autologous DC pulsed with tumor Ag Methods Generate DC in vitro from circulating precursors Load DC with Ag Return DC to patients Edgar Engleman
8 Dendritic Cell Based Vaccines in Cancer Treatment Leukapheresis DC Generation (GM-CSF, IL-4) DC Maturation (TNF, CD40-L) Tumor Antigen Vaccination (Intratumoral) Ag loading Immune & Clinical Monitoring Vaccination (systemic) Antigen-Pulsed DC
9 Problems with Customized DC Vaccines Poor efficacy -- most tumor bearing patients do not respond Best tumor Ags, DC activation method, route of delivery all unknown Cost and complexity are high
10 A New Approach to Vaccination 1. Receptor-mediated antigen targeting to dendritic cells in peripheral lymphoid tissues. 2. Simultaneous maturation of the antigencapturing dendritic cells.
11 DEC-205, a Homologue of the Macrophage Mannose Receptor, with 10 vs 8 External, Contiguous, C-type Lectin Domains 1. Available mab to DEC High expression by lymph node DCs of DEC Rapid targeting of mab to DCs in lymph nodes including distal tissues. 4. Access to MHC class I & II MMR DEC-205 Jiang et al, Nature 375: (1995)
12 DEC-205 on Dendritic Cells in the T Cell Areas of Mouse Lymph Nodes B B T
13 Rapid, Efficient and Durable Targeting of αdec-205 Antibodies to DCs, systemically, in situ C57BL/6 10 µg αdec-205:alexa 488 or isotype control (s.c.) Draining Distal Spleen nodes Isotype 30min minutes to 3 days 6 hrs. 15 hrs Harvest draining/distal nodes and spleen Enrich for CD11c + Evaluate: αdec-205 targeting kinetics Subset targeting αdec-205 CD8α 3 days
14 Targeting Dendritic Cells with α-dec-205:ova Markedly Enhances Presentation to CD4 + and CD8 + T cells (CFSE-labeled) in vivo in the Steady State Control OT-I (CD8 + ) OT-I OVA OT-II PBS Iso.:OVA 250,000 ng 25,000 ng OT-II (CD4 + ) 2,500 ng PBS Monovalent αdec-205:ova Iso.:OVA 250 ng % Max. Count 50 ng 2 ng CFSE
15 A Single Vaccination with α-dec-205:ova + α-cd40 Induces CD8 + T Cell Immunity of Greater Magnitude (and Duration) than Current Gold Standards Lymph node Spleen Naïve Ex vivo pulsed spleen DC Day 7 Day 30 OVA + CFA αdec-205:ova + αcd40 1.3% 0.75% 3.0% 7.0% % IFNγ + CD8 + Lymphocytes
16 Vaccination with α-dec-205:ova + α-cd40, but not DC-OVA or OVA / CFA, Exerts a Therapeutic Effect on 7 Day Tumors 400 Tumor area (mm 2 ) PBS αcd40 OVA + CFA αdec-205:ova + αcd40 Ex vivo OVA-pulsed DCs Time After Treatment (days) Initial tumor area (OVA-B16)
17 β-catenin signaling in determining DC function β-catenin activation leads to DC maturation without the production of cytokines β-catenin activation in DCs leads to CD4 + T cell tolerance in models of autoimmune disease.
18 Targeted deletion/activation of β-catenin in DCs Pathway inactivation: β-cat -/- (CD11c-Cre β-cat FL/FL ) Pathway activation: β-cat active (CD11c-Cre β-catexon3 FL/FL ) Tolerance Immunity Sonja Zahner Bjoern Clausen
19 Whether tumors activate β-catenin in DCs? Splenic DCs of tumor-bearing mice WT-T WT β-catenin
20 β-catenin activation and tumor-bearing mice exhibited suppressed CD8 recall responses
21 How activation of β-catenin in DCs affects anti-tumor CD8 T cell immunity? αdec-ova (CpG) 3, 5, 8 days 3 days Naïve CFSE + OT1 In vitro restimulation
22 Tumor-mediated inhibition of crosspriming is β-catenin-dependent. αdec-ova (CpG) 3 days 3 days Naïve CFSE + OT1 In vitro restimulation
23 Tumor-bearing β-catenin -/- mice exhibited normal CD8 memory responses when transferred into WT mice
24 Blocking β-catenin reversed tumor-induced inhibition of cross-priming
25 β-catenin active DCs exhibited increased FOXO3 expression and reduced NF-kB activation upon TLR signaling
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